Current Reviews in Clinical and Experimental Pharmacology最新文献

Background: Poisoning is one of the leading causes of childhood morbidity and mortality worldwide. Despite the advancement of poison detection by modern investigation methods, the clinical skill of toxidrome recognition by combining the findings from a detailed history, thorough physical examination, and the results of basic investigations is still indispensable for the management of children with suspected poisoning.

Objective: The aim was to review pediatric toxidromes and poisoning management.

Methods: A literature search was conducted on PubMed (between February 1 and 15, 2020) with keywords "toxidrome" "poisoning" "intoxication" "children" and "pediatric". The search was customized by applying the appropriate filters so as to get the most relevant articles to meet the objective of this review article.

Results: Toxidrome recognition may offer a quick guide to possible toxicology diagnosis so that specific antidote can be administered in a timely manner. This article discusses a few commonly encountered toxidromes in pediatric poisoning, with an emphasis on the symptomatology and source of exposure. The antidote and specific management for each toxidrome are also discussed. Although most patients with intoxication can be managed with close observation, supportive measures and antidote treatment, it is unfortunate that antidotes are only available for a limited number of poisons responsible for intoxication. Extracorporeal toxin removal is being increasingly recognized as a mode of treatment for patients with rapid deterioration who are unresponsive to conventional management. The decision to apply such technique and the choice of modality are frequently individualized due to the paucity of high-level evidence. The various patient and toxin/medication factors involved in the decision- making process are discussed.

Conclusion: Poisoning is a common cause of pediatric accidents and injuries. Physicians should be familiar with common toxidromes and poisoning management.

Background: The prevalence of cholelithiasis in developed countries is high and its cause is multifactorial, with a negligible proportion of drug-induced cholelithiasis.

Methods: Relevant studies were identified by PubMed, Google Scholar and Science Direct. Reference lists of retrieved articles were also reviewed. The most relevant and up-to-date information was incorporated.

Results: There is a wide range of drugs that can induce lithiasis. While the risk of developing lithiasis is high with some drugs (ceftriaxone, atazanavir, somatostatin analogues), it is lower or even questionable with others. Some drugs precipitate in the bile and may account for up to 100% of the weight of the stone.

Conclusion: Cholelithiasis can be induced by a wide range of drugs with different mechanisms of action. The aim of the article is to draw attention to this lesser known fact and the need to take into account the risk of developing lithiasis prior to therapy initiation.

While facing potentially high morbidity from COVID-19 without known effective therapies, the off-label use of several non-specific drugs has been advocated, including re-purposed anti- viral (e.g., remdesivir or the lopinavir/ritonavir combination), biologic agents (e.g., tocilizumab), and antimalarial drugs such as chloroquine and hydroxychloroquine, in association with or without azithromycin. Data regarding the effectiveness of these drugs in treating COVID-19 has been shown in some trials and clinical settings, but further randomised controlled trials are still being carried out. One of the main concerns regarding their widespread use, however, is their possible effects on the QT interval and arrhythmogenic potential. Some of these drugs have been associated with QT prolongation and Torsades de Point, a potentially lethal ventricular arrhythmia. The review aims to highlight the magnitude of this problem, to quickly refresh clinically impacting cornerstones of QT interval and TdP pathophysiology, to summarize the available evidence regarding the QT and arrhythmia impact of drugs used in different clinical settings in COVID-19 patients, and to help the physicians dealing with the knowledge needed in the everyday clinical duties in case of doubts regarding QT-induced arrhythmias in this time of emergency.

Background: Signal strength for any drug-event combination can be determined using disproportionality analysis. Vemurafenib is a BRAF inhibitor approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of metastatic melanoma. This study aims to identify the signal strength of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) associated with vemurafenib using disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS).

Methods: Data were obtained from the public release of data in FAERS. The case/non-case method was adopted for the analysis of the association between vemurafenib use and DRESS. The data mining algorithm used for the analysis was the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). A value of ROR-1.96SE>1, PRR≥2 was considered as positive signal strength.

Results: A total of 7,171 reports for DRESS have been reported in the FDA database. Amongst which, 125 reports were associated with vemurafenib. A cumulative ROR of 17.72 (95% CI 14.83; 21.18) and PRR of 17.46 (95% CI 14.65; 20.81) were observed. Combination treatment of vemurafenib with cobimetinib had a higher number of reports (100) with ROR of 103.42 (84.13- 127.14) and PRR of 94.52 (78.26- 114.15). Four deaths were reported and the non-death serious reports included hospitalization, life-threatening, disability, and other serious events with 61, 11, 2 and 39 reports, respectively.

Conclusion: Positive signal strength was observed for vemurafenib associated DRESS. The signal strength was higher for vemurafenib in combination with cobimetinib than vemurafenib alone. Health care professionals should be cautious about encountering serious adverse events and should report such events to the regulatory authorities.

Background: Rocuronium is a muscle relaxant with increased use due to its binding relation with the reversal agent sugammadex. The purpose of this review entails the investigation of its use for the maintenance of Deep Neuromuscular Block (NMB) via continuous infusion.

Methods: Based on PRISMA systematic search guidelines, databases included PubMed, ISI Web of Science, Cochrane Library and Google Scholar. This comprehensive search addresses surgical patients under deep muscle relaxation via continuous rocuronium infusion. The main indicators were the rocuronium administration, NMB monitoring approaches and effects in order to maintain the deep level of relaxation, as well as reversal time after a standard dose of sugammadex.

Results: Despite the variance in approaches found in the literature, findings show the overall maintenance of deep NMB requires approximately 0.758 mg.kg^-1h^-1 of rocuronium (according to the PTC target of 0-10, 0-5 and 1-2, mean estimates are 0.445, 0.65 and 0.833 mg.kg^-1h^-1 respectively), suggesting that a lower range and a smaller maximum of PTC response require higher amount of rocuronium for its maintenance. The standard dose of sugammadex (4 mg/kg), administered at the end of the surgery takes longer [2.85 (1.17) min] than when they are administered after moderate NMB recovery [1.68 (0.47) min].

Conclusion: Continuous infusion for deep NMB presents inherent advantages in terms of maintenance and stability of muscle relaxation. Monitoring and rocuronium administration approaches are fundamental and intrinsically connected to provide a stable and improved maintenance of deep NMB.

Background: Our study aims at assessing the pre-clinical impact of the synergistic mechanism of Daptomycin (DAP) and Ceftaroline (CFT) on patients with Methicillin-Resistant Staphylococcus aureus Bacteremia infections (MRSAB).

Methods: A systematic overview was conducted by searching PubMed, Oxford academic, and Cochrane library up to June 2020.

Study selection and data extraction: All English- language clinical trials, in vitro studies, and case reports related to the synergistic drug therapy for MRSAB.

Results: In the case of MRSAB infections, we examined two different in vitro studies that showed effective synergism with DAP and CFT. The Minimum Inhibitory Concentration (MIC) range observed for each is as follow: DAP 0.125-1 mg/L, CFT 0.38-1 mg/L, DAP + CFT 0.094-0.5 mg/L, vancomycin (VAN) 0.75-2 mg/L, VAN + CFT 0.25-2 mg/L. DAP + CFT combination displayed the most efficacy with the lowest MIC. The statistical analysis performed showed that DAP + CFT obtained significantly lower fractional inhibitory concentration (FIC) values (0.941 ± 0.328) compared with VAN + CFT. In vitro activities of regimens tested on DAP non-susceptibility and VAN intermediate after 96 hours showed DAP 8.29 ± 0.03^a log₁₀ CFU/mL, VAN 6.82 ± 0.04^a log₁₀ Colony Forming Unit (CFU)/mL, CFT 4.63 ± 0.19^a log₁₀ CFU/mL, DAP + CFT 1.15 ± 0.20^b log₁₀ CFU/mL, VAN + CFT 3.18 ± 0.49^a log₁₀ CFU/mL. (^a meaning significantly different than DAP plus CFT, P< equal to 0.001^b meaning therapeutic enhancement combination was defined as ≥ 2 log₁₀ CFU/ml reduction over the most active single agent). Based on these results, although DAP was not susceptible, the Colony Forming Unit (CFU) for DAP and CFT had the best therapeutic results.

Conclusion: In vitro studies have shown that a combination DAP and CFT is more efficacious than the combination of VAN and CFT in MRSA bacteremia infections. The synergic effects of DAP (bactericidal) and CFT (bactericidal) is statistically significant, in recent trials, warranting promising evidence for its use in complicated bacteremia infection.

Background: Helicobacter pylori (H. pylori) infection is the most common cause of peptic ulcer disease and it can be associated with many complications, including malignancies. In clinical practice, some clinicians may use Clavulanic Acid (CA) in combination with amoxicillin or other beta-lactams as an addition to the standard treatment regimens. This practice may be done by habitual mistake, non-evidence based hypothetical assumptions, or by prescribing it as an alternative treatment. This review aims to expose the effect of CA against H. pylori infection and to review the possible mechanisms that may contribute to that effect.

Methods: A PubMed and Google Scholar literature search was obtained on both pre-clinical and clinical studies related to CA and H. pylori infection.

Results: Available clinical studies showed improvement in the eradication of H. pylori by about 10- 20% when CA was added to the treatment regimens. This effect for CA could be related to several mechanisms including inhibition of H. pylori growth by binding to Penicillin-Binding Proteins (PBPs), the transformation of H. pylori from the active filamentous form into coccoidal form, induction of the release of dopamine, modulation of immunological response towards H. pylori infection and its relationship with other microbiota. Randomized-controlled studies on patients with resistance to H. pylori are needed. Moreover, in vitro studies to evaluate the mechanisms by which CA may influence H. pylori are warranted.

Conclusion: The presented literature suggests potential avenues for the use of CA in the management of peptic ulcer disease and H. pylori infection.

Background: It was previously thought that inflammation and an immune response were the only factors capable of causing IL-1β, IL-6 and other cytokine`s production. In recent years data have appeared that stressful effects can also occupy an important place, enhancing production of IL- 1β, IL-6 and other cytokines; the result will be a change in the functional activity of a particular cell element, for example immunocompetent cells with subsequent development of inflammation, or a change in the functional activity of neurons. This experiment is aimed at studying the effect of the Selank glyprolin neuropeptide drug on the level of cytokines in animals under conditions of "social" stress, the results of which indicate the presence of stress-protective activity.

Methods: White nonlinear rats were used as experimental animals. A model of confrontations between males was chosen to create a "social" stress. The animals were in pairs in a cage which were separated by a septum preventing physical contact but having openings that provide sensory contact. Each day, the septum was removed for 10 minutes leading in an overwhelming majority to agonistic collisions (confrontations). Laboratory animals were divided into 3 groups: a group of intact males, a group of animals that were subjected to stress (sensory contact) for 20 days and a group that received intraperitoneally Selank at a dose of 100 mcg/kg/day under conditions of 20-day stress. The level of cytokines under study was determined by enzyme-linked immunosorbent assay.

Results: As a result of the work performed to determine the concentration of pro-inflammatory and anti- inflammatory cytokines, it was found that in the serum of animals exposed to stress, there was a statistically significant increase in the level of IL-1β, IL-6 and TGF-β1 in individuals with both types of behavior. It should be noted that, under the conditions of this stressful impact, there was a tendency to decrease the concentration of IL-4 and increase the level of TNF-α but these indicators were not statistically significant. Evaluation of the effect of Semax on the level of the cytokines in a stress-induced state showed that this neuropeptide causes a decrease in the concentration of IL-1β and IL-6, restoration of the level of IL-4, as well as suppression of the production of TGF-β1 and TNF-α in these conditions.

Conclusion: This peptide is able to reduce the concentration of IL-1β, IL-6 and TNF-α, as well as TGF-β1, practically reaching control values, when studying the effect of Selank on the level of cytokines under conditions of " social" stress. There is the need for a detailed study of the role of cytokines in the development of stress-induced changes in order to find optimal correction tools.

Background/objective: Tacrolimus HEXAL®/Crilomus® is an approved generic immunosuppressant for the prevention and treatment of rejection following renal transplantation. For safe and socioeconomically efficient conversion of the innovator into a generic formulation, high- -quality data are necessary, in view of the different and country-specific comorbidities and pharmacokinetics in kidney transplant recipients.

Patients and methods: From 2014 to 2017, we enrolled 32 kidney transplant recipients, receiving newly prescribed Tacrolimus HEXAL®/Crilomus® in 5 German centers. Efficacy and safety data were collected over 6-8 months and retrospectively compared to the period prior to conversion.

Results: The mean tacrolimus trough level was 4.91 ng/mL Standard Deviation (SD) (SD ±1.7) before and 5.06 ng/mL (SD ±1.97) after conversion. Mean tacrolimus trough concentration-dose-ratio (+/- SD) was 187.1 ng/mL/mg/kg/day (SD 99.2) for the reference and 205.1 ng/mL/mg/kg/day (SD 133) for the generic product, resulting in a non-significant difference of 18.0 ng/mL/mg/kg/day (SD 71.8) (p=0.84, Wilcoxon V=180). Overall, dosing had to be changed in 4 (14.8%) patients. Graft function remained stable and no rejections occurred.

Conclusion: In conclusion, conversion to the generic tacrolimus formulation can be considered safe and feasible in long-term kidney transplant recipients in Germany. As suggested by guidelines, vigilant therapeutic drug monitoring is recommended to account for possible tacrolimus concentration variability on the individual patient level.

Background: Interleukin-1 (IL-1) is a pro-inflammatory cytokine that is produced by endothelial cells, smooth muscle cells, and macrophages. It is an important regulator of a complex humoral and cellular inflammatory response. IL-1β is known to be implicated in the development of chronic inflammatory disorders such as rheumatoid arthritis. We aimed to review the effects of IL-1β antagonists in various cardiovascular disorders and to discuss their effectiveness in such diseases.

Methods: Major biomedical databases, including PubMed and Scopus, were searched for clinical studies regarding the treatment of cardiovascular diseases (CVD) using IL-1β antagonists.

Results: The drugs currently used in clinical trials are anakinra, the monoclonal antibodies canakinumab and gevokizumab, and the soluble decoy receptor rilonacept. There are clinical trials and case reports of patients with CVD in which anakinra administration, at the standard dose, has caused rapid clinical improvement and recovery in a few months. Our comprehensive search revealed that IL-1β antagonists have beneficial effects in the treatment of various cardiovascular disorders such as myocarditis, pericarditis, heart failure, acute coronary syndrome, myocardial infarction, atherosclerosis, and Kawasaki disease.

Conclusion: The present review article shows that IL-1β has a major role in the pathophysiology of cardiovascular disorders, its antagonists have beneficial effects in these conditions, and their use should be considered in future studies.